Prediction of melanoma metastasis by the Shields index based on lymphatic vessel density

<p>Abstract</p> <p>Background</p> <p>Melanoma usually presents as an initial skin lesion without evidence of metastasis. A significant proportion of patients develop subsequent local, regional or distant metastasis, sometimes many years after the initial lesion was removed. The current most effective staging method to identify early regional metastasis is sentinel lymph node biopsy (SLNB), which is invasive, not without morbidity and, while improving staging, may not improve overall survival. Lymphatic density, Breslow's thickness and the presence or absence of lymphatic invasion combined has been proposed to be a prognostic index of metastasis, by Shields et al in a patient group.</p> <p>Methods</p> <p>Here we undertook a retrospective analysis of 102 malignant melanomas from patients with more than five years follow-up to evaluate the Shields' index and compare with existing indicators.</p> <p>Results</p> <p>The Shields' index accurately predicted outcome in 90% of patients with metastases and 84% without metastases. For these, the Shields index was more predictive than thickness or lymphatic density. Alternate lymphatic measurement (hot spot analysis) was also effective when combined into the Shields index in a cohort of 24 patients.</p> <p>Conclusions</p> <p>These results show the Shields index, a non-invasive analysis based on immunohistochemistry of lymphatics surrounding primary lesions that can accurately predict outcome, is a simple, useful prognostic tool in malignant melanoma.</p

Coherent matter wave inertial sensors for precision measurements in space

We analyze the advantages of using ultra-cold coherent sources of atoms for matter-wave interferometry in space. We present a proof-of-principle experiment that is based on an analysis of the results previously published in [Richard et al., Phys. Rev. Lett., 91, 010405 (2003)] from which we extract the ratio h/m for 87Rb. This measurement shows that a limitation in accuracy arises due to atomic interactions within the Bose-Einstein condensate

Hybrid Mechanical Systems

We discuss hybrid systems in which a mechanical oscillator is coupled to another (microscopic) quantum system, such as trapped atoms or ions, solid-state spin qubits, or superconducting devices. We summarize and compare different coupling schemes and describe first experimental implementations. Hybrid mechanical systems enable new approaches to quantum control of mechanical objects, precision sensing, and quantum information processing.Comment: To cite this review, please refer to the published book chapter (see Journal-ref and DOI). This v2 corresponds to the published versio

Mitochondrial echoes of first settlement and genetic continuity in El Salvador

Background: From Paleo-Indian times to recent historical episodes, the Mesoamerican isthmus played an important role in the distribution and patterns of variability all around the double American continent. However, the amount of genetic information currently available on Central American continental populations is very scarce. In order to shed light on the role of Mesoamerica in the peopling of the New World, the present study focuses on the analysis of the mtDNA variation in a population sample from El Salvador. Methodology/Principal Findings: We have carried out DNA sequencing of the entire control region of the mitochondrial DNA (mtDNA) genome in 90 individuals from El Salvador. We have also compiled more than 3,985 control region profiles from the public domain and the literature in order to carry out inter-population comparisons. The results reveal a predominant Native American component in this region: by far, the most prevalent mtDNA haplogroup in this country (at ~90%) is A2, in contrast with other North, Meso- and South American populations. Haplogroup A2 shows a star-like phylogeny and is very diverse with a substantial proportion of mtDNAs (45%; sequence range 16090–16365) still unobserved in other American populations. Two different Bayesian approaches used to estimate admixture proportions in El Salvador shows that the majority of the mtDNAs observed come from North America. A preliminary founder analysis indicates that the settlement of El Salvador occurred about 13,400±5,200 Y.B.P.. The founder age of A2 in El Salvador is close to the overall age of A2 in America, which suggests that the colonization of this region occurred within a few thousand years of the initial expansion into the Americas. Conclusions/Significance: As a whole, the results are compatible with the hypothesis that today's A2 variability in El Salvador represents to a large extent the indigenous component of the region. Concordant with this hypothesis is also the observation of a very limited contribution from European and African women (~5%). This implies that the Atlantic slave trade had a very small demographic impact in El Salvador in contrast to its transformation of the gene pool in neighbouring populations from the Caribbean facade

A cardinal role for cathepsin D in co-ordinating the host-mediated apoptosis of macrophages and killing of pneumococci

The bactericidal function of macrophages against pneumococci is enhanced by their apoptotic demise, which is controlled by the anti-apoptotic protein Mcl-1. Here, we show that lysosomal membrane permeabilization (LMP) and cytosolic translocation of activated cathepsin D occur prior to activation of a mitochondrial pathway of macrophage apoptosis. Pharmacological inhibition or knockout of cathepsin D during pneumococcal infection blocked macrophage apoptosis. As a result of cathepsin D activation, Mcl-1 interacted with its ubiquitin ligase Mule and expression declined. Inhibition of cathepsin D had no effect on early bacterial killing but inhibited the late phase of apoptosis-associated killing of pneumococci in vitro. Mice bearing a cathepsin D-/- hematopoietic system demonstrated reduced macrophage apoptosis in vivo, with decreased clearance of pneumococci and enhanced recruitment of neutrophils to control pulmonary infection. These findings establish an unexpected role for a cathepsin D-mediated lysosomal pathway of apoptosis in pulmonary host defense and underscore the importance of apoptosis-associated microbial killing to macrophage function

Functional Interchangeability of Late Domains, Late Domain Cofactors and Ubiquitin in Viral Budding

The membrane scission event that separates nascent enveloped virions from host cell membranes often requires the ESCRT pathway, which can be engaged through the action of peptide motifs, termed late (L-) domains, in viral proteins. Viral PTAP and YPDL-like L-domains bind directly to the ESCRT-I and ALIX components of the ESCRT pathway, while PPxY motifs bind Nedd4-like, HECT-domain containing, ubiquitin ligases (e.g. WWP1). It has been unclear precisely how ubiquitin ligase recruitment ultimately leads to particle release. Here, using a lysine-free viral Gag protein derived from the prototypic foamy virus (PFV), where attachment of ubiquitin to Gag can be controlled, we show that several different HECT domains can replace the WWP1 HECT domain in chimeric ubiquitin ligases and drive budding. Moreover, artificial recruitment of isolated HECT domains to Gag is sufficient to stimulate budding. Conversely, the HECT domain becomes dispensable if the other domains of WWP1 are directly fused to an ESCRT-1 protein. In each case where budding is driven by a HECT domain, its catalytic activity is essential, but Gag ubiquitination is dispensable, suggesting that ubiquitin ligation to trans-acting proteins drives budding. Paradoxically, however, we also demonstrate that direct fusion of a ubiquitin moiety to the C-terminus of PFV Gag can also promote budding, suggesting that ubiquitination of Gag can substitute for ubiquitination of trans-acting proteins. Depletion of Tsg101 and ALIX inhibits budding that is dependent on ubiquitin that is fused to Gag, or ligated to trans-acting proteins through the action of a PPxY motif. These studies underscore the flexibility in the ways that the ESCRT pathway can be engaged, and suggest a model in which the identity of the protein to which ubiquitin is attached is not critical for subsequent recruitment of ubiquitin-binding components of the ESCRT pathway and viral budding to proceed

Socioeconomic questionnaire and clinical assessment in the HELENA Cross-sectional Study: methodology

Rationale: Environmental factors such as dietary habits, breastfeeding, socioeconomic conditions and educational factors are strong influences on nutritional and puberty status, physical activity, food choices and their interactions. Several diseases of adulthood seem to be linked to, or to originate from, lifestyle in childhood and adolescence. Objective: The aims of this study are to describe birth parameters and socioeconomic factors and to assess clinical status in adolescents aged 13-16 years from 10 European countries participating in the Healthy Lifestyle in Europe by Nutrition in Adolescence (HELENA) Cross-Sectional Study (CSS). Methodology: A self-report questionnaire on the socioeconomic status, a parental questionnaire concerning neonatal period and also a case report form (CRF), in which clinical items during clinical examination (such as medical history, treatments, anthropometry, Tanner staging, blood pressure, heart rate) were assessed. To develop these documents, first a list of items was established, a search of existing documents was performed and the advice of local and international experts was taken. All documents (questionnaires and an operations manual) were discussed in plenary HELENA meetings; a final version of these documents was fixed, and the process of translation and back translation was performed. Results: The questionnaires and CRF were tested for validation in all 10 participant cities; 208 adolescents were enrolled during the pilot study. All items that caused problems or questions in one or more participating centers or were completed by < 85% of the adolescents were reviewed before the beginning of the HELENA-CSS. Conclusion: These final questionnaires and CRF will contribute to better understanding of the inequalities in nutrition, behavior and health in the European adolescent population. The experience and process should be useful for other multicenter studies

Effective use of cerium anomalies as a redox proxy in carbonate-dominated marine settings

Rare earth elements and yttrium (REY) have a distinct distribution pattern in seawater, and this pattern may be faithfully preserved in carbonate sediments and rocks. Anomalous concentrations of redox-sensitive cerium (Ce) compared with neighbouring REY originate in oxic water column conditions, and as such, Ce anomalies can provide a potentially useful redox proxy in carbonate-dominated marine settings. The methods used to extract REY from carbonates vary widely, and may suffer from widespread leaching of REY from accessory non-carbonate minerals and organic matter, limiting the application of Ce anomalies for palaeo-redox reconstruction. We have systematically compared different methods on 195 carbonate samples with varying purity (% carbonate) from both modern and ancient environments. We used sequential leaching experiments in nitric acid to identify the most ‘seawater-like’ portion of the carbonate sample where contributions from non-carbonate minerals and organic matter are minimised. We also compared the results of sample dissolution in different types and strengths of acid. Our results confirm that REY concentrations can be inadvertently contaminated by partial leaching of clays and Fe (oxyhydr)oxides during a single-step digestion, and we suggest a pre-leach of 20% of the sample, followed by a partial leach of 40% of the sample to selectively dissolve carbonate. We suggest that REY studies are optimised in carbonates with > 85% CaCO₃, and show that dolomites behave differently during the leaching process and must be treated separately. We present REY patterns for modern carbonate-rich sediments from a range of environments, and show that seawater REY are faithfully preserved in some non-skeletal carbonate, but modified leaching procedures are necessary for impure, unlithified or organic rich carbonate sediments. We combine REY with Fe-speciation data to identify how Fe oxides and clays contribute to the REY signal and explore how the two proxies can be used together to provide a complex and high-resolution redox reconstruction in carbonate-dominated marine environments

EGFR interacts with the fusion protein of respiratory syncytial virus strain 2-20 and mediates infection and mucin expression.

Respiratory syncytial virus (RSV) is the major cause of viral lower respiratory tract illness in children. In contrast to the RSV prototypic strain A2, clinical isolate RSV 2-20 induces airway mucin expression in mice, a clinically relevant phenotype dependent on the fusion (F) protein of the RSV strain. Epidermal growth factor receptor (EGFR) plays a role in airway mucin expression in other systems; therefore, we hypothesized that the RSV 2-20 F protein stimulates EGFR signaling. Infection of cells with chimeric strains RSV A2-2-20F and A2-2-20GF or over-expression of 2-20 F protein resulted in greater phosphorylation of EGFR than infection with RSV A2 or over-expression of A2 F, respectively. Chemical inhibition of EGFR signaling or knockdown of EGFR resulted in diminished infectivity of RSV A2-2-20F but not RSV A2. Over-expression of EGFR enhanced the fusion activity of 2-20 F protein in trans. EGFR co-immunoprecipitated most efficiently with RSV F proteins derived from "mucogenic" strains. RSV 2-20 F and EGFR co-localized in H292 cells, and A2-2-20GF-induced MUC5AC expression was ablated by EGFR inhibitors in these cells. Treatment of BALB/c mice with the EGFR inhibitor erlotinib significantly reduced the amount of RSV A2-2-20F-induced airway mucin expression. Our results demonstrate that RSV F interacts with EGFR in a strain-specific manner, EGFR is a co-factor for infection, and EGFR plays a role in RSV-induced mucin expression, suggesting EGFR is a potential target for RSV disease

Multiwavelength observations of short time-scale variability in NGC 4151. IV. Analysis of multiwavelength continuum variability

This paper combines data from the three preceding papers in order to analyze the multi-waveband variability and spectral energy distribution of the Seyfert~1 galaxy NGC~4151 during the December 1993 monitoring campaign. The source, which was near its peak historical brightness, showed strong, correlated variability at X-ray, ultraviolet, and optical wavelengths. The strongest variations were seen in medium energy ($\sim$1.5~keV) X-rays, with a normalized variability amplitude (NVA) of 24\%. Weaker (NVA = 6\%) variations (uncorrelated with those at lower energies) were seen at soft $\gamma$-ray energies of $\sim$100~keV. No significant variability was seen in softer (0.1--1~keV) X-ray bands. In the ultraviolet/optical regime, the NVA decreased from 9\% to 1\% as the wavelength increased from 1275~\AA\ to 6900~\AA. These data do not probe extreme ultraviolet (1200~\AA\ to 0.1~keV) or hard X-ray (2--50~keV) variability. The phase differences between variations in different bands were consistent with zero lag, with upper limits of \ls0.15~day between 1275~\AA\ and the other ultraviolet bands, \ls0.3~day between 1275~\AA\ and 1.5~keV, and \ls1~day between 1275~\AA\ and 5125~\AA. These tight limits represent more than an order of magnitude improvement over those determined in previous multi-waveband AGN monitoring campaigns. The ultraviolet fluctuation power spectra showed no evidence for periodicity, but were instead well-fitted with a very steep, red power-law ($a = -2.5$). If photons emitted at a ``primary" waveband are absorbed by nearby material and ``reprocessed" to produce emission at a secondary waveband, causality arguments require that variations in the secondary band follow those in the primary band. The tight interband correlation and limits on the ultraviolet andComment: 35 pages, LaTeX (including aaspp4), including 7 PostScript figures; To appear in the ApJ (October 20, 1996) Vol. 47